RESUMO
In order to study the neuroprotective mechanism of cinnamaldehyde on reserpine-induced Parkinson's disease(PD) rat models, 72 male Wistar rats were randomly divided into blank group, model group, Madopar group, and cinnamaldehyde high-, medium-, and low-dose groups. Except for the blank group, the other groups were intraperitoneally injected with reserpine of 0.1 mg·kg~(-1) once every other morning, and cinnamaldehyde and Madopar solutions were gavaged every afternoon. Open field test, rotarod test, and oral chewing movement evaluation were carried out in the experiment. The brain was taken and fixed. The positive expression of dopamine receptor D1(DRD1) was detected by TSA, and the changes in neurotransmitters such as dopamine(DA) and 3,4-dihydroxyphenylacetic acid(DOPAC) in the brain were detected by enzyme-linked immunosorbent assay(ELISA). The protein and mRNA expression levels of tyrosine hydroxylase(TH) and α-synuclein(α-Syn) in substantia nigra(SN) were detected by RT-PCR and Western blot. The results showed that after the injection of reserpine, the hair color of the model group became yellow and dirty; the arrest behavior was weakened, and the body weight was reduced. The spontaneous movement and exploration behavior were reduced, and the coordination exercise ability was decreased. The number of oral chewing was increased, but the cognitive ability was decreased, and the proportion of DRD1 positive expression area in SN was decreased. The expression of TH protein and mRNA was down-regulated, and that of α-Syn protein and mRNA was up-regulated. After cinnamaldehyde intervention, it had an obvious curative effect on PD model animals. The spontaneous movement behavior, the time of staying in the rod, the time of movement, the distance of movement, and the number of standing times increased, and the number of oral chewing decreased. The proportion of DRD1 positive expression area in SN increased, and the protein and mRNA expression levels of α-Syn were down-regulated. The protein and mRNA expression levels of TH were up-regulated. In addition, the levels of DA, DOPAC, and homovanillic acid(HVA) neurotransmitters in the brain were up-regulated. This study can provide a new experimental basis for clinical treatment and prevention of PD.
Assuntos
Acroleína/análogos & derivados , Doença de Parkinson , Ratos , Masculino , Animais , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Reserpina/efeitos adversos , Reserpina/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Ratos Wistar , Substância Negra/metabolismo , RNA Mensageiro/metabolismo , Neurotransmissores/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
INTRODUCTION: Nociplastic pain involves reflexive and nonreflexive pain responses and it is a core symptom of fibromyalgia (FM). The increasing prevalence of this health condition and the low rates of patients' quality of life, combined with the lack of suitable pharmacologic treatments, evidence the demand to research new alternatives. Polyphenols may be potential therapeutic candidates as they have been reported to exert pathological pain modulation in preclinical models. In that context, this work was aimed to study the antinociceptive effects of a polyphenolic extract obtained from decaffeinated ground roasted coffee, in the RIM6 FM-like mouse model. METHODS: To this end, RIM6 adult ICR-CD1 female mice were administered daily once a week with either 10 or 15 mg/kg of extract, and reflexive pain responses were evaluated for up to 3 weeks. At the end, the depressive-like behavior was assessed as a nonreflexive pain response, and spinal cord and serum samples were collected for immunohistochemical and toxicological analyses. RESULTS: These findings showed that the repeated administration of the coffee polyphenolic extract (CE) modulated reflexive pain responses, depressive-like behavior, and spinal cord gliosis in a dose-dependent manner, without signs of systemic toxicity. CONCLUSION: Thus, the CE may be a potential pharmacological treatment suitable to relieve nociplastic pain responses characteristic of FM.
Assuntos
Dor Crônica , Fibromialgia , Humanos , Feminino , Camundongos , Animais , Fibromialgia/tratamento farmacológico , Fibromialgia/induzido quimicamente , Reserpina/efeitos adversos , Hiperalgesia/tratamento farmacológico , Qualidade de Vida , Camundongos Endogâmicos ICRRESUMO
Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.
Assuntos
Fibromialgia , Mastocitose , Camundongos , Masculino , Animais , Fibromialgia/metabolismo , Mastócitos/metabolismo , Hiperalgesia/metabolismo , Serotonina/metabolismo , Reserpina/efeitos adversos , Mastocitose/metabolismo , Mastocitose/patologiaRESUMO
BACKGROUND: Spleen deficiency syndrome (SDS) is associated with elevated inflammatory factors and dysregulation of gastrointestinal motility hormones and intestinal microbiota. Qushi decoction (QD), a traditional formula, has not been reported using modern scientific research methods for changes in its probiotic fermented QD (FQD) composition and its potential mechanisms to alleviate SDS. Therefore, the aim of this study was to investigate the splenic protection of FQD in SDS rats by modulating gastrointestinal motility hormones and intestinal microbiota. RESULTS: The results showed that FQD increased total polysaccharides, total protein, total flavonoids and the other active ingredients compared to QD, effectively improved splenic inflammation and apoptosis in SDS rats, and modulated gastrointestinal motility hormones to alleviate diarrhea and other symptoms. In addition, the dysregulation of the gut microbiota was reversed by increasing the levels of Bifidobacterium and decreasing the levels of Escherichia-Shigella and Proteobacteria, which may be related to the regulation of bacterial metabolites to alleviate SDS. CONCLUSION: These results suggest that FQD is an effective formula for improving SDS. Our findings show that FQD beneficial to the implications for the treatment of SDS. © 2023 Society of Chemical Industry.
Assuntos
Microbioma Gastrointestinal , Probióticos , Esplenopatias , Ratos , Animais , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Reserpina/efeitos adversos , Probióticos/farmacologia , Esplenopatias/induzido quimicamente , Esplenopatias/tratamento farmacológico , Hormônios/efeitos adversosRESUMO
Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D1-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats. Reserpine-treated animals were intrathecally injected with different dopamine receptors agonists and antagonists, and small interfering RNAs (siRNAs) against D1 and D5 receptor subtypes. Withdrawal and muscle pressure thresholds were assessed with von Frey filaments and the Randall-Selitto test, respectively. Expression of D1-like receptors in lumbar spinal cord and dorsal root ganglion was determined using real time polymerase chain reaction (qPCR). Reserpine induced tactile allodynia and muscle hyperalgesia. Intrathecal dopamine and D1-like receptor agonist SKF-38393 induced nociceptive hypersensitivity in naïve rats, whilst this effect was prevented by the D1-like receptor antagonist SCH-23390. Moreover, SCH-23390 induced a sex-dependent antiallodynic effect in reserpine-treated rats. Furthermore, transient silencing of D1 and D5 receptors significantly reduced reserpine-induced hypersensitivity in female rats. Reserpine slightly increased mRNA D5 receptor expression in dorsal spinal cord, but not in DRG. This work provides new insights about the involvement of the spinal dopaminergic D1/D5 receptors in reserpine-induced hypersensitivity in rats.
Assuntos
Fibromialgia , Ratos , Feminino , Animais , Fibromialgia/induzido quimicamente , Dopamina/fisiologia , Reserpina/efeitos adversos , Ratos Wistar , Dor/induzido quimicamente , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Receptores Dopaminérgicos , Receptores de Dopamina D1/agonistasRESUMO
BACKGROUND: Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that reserpine causes depression. This assumption was a foundation for the original monoamine hypothesis of depression. However, there remains conflicting evidence as to whether reserpine causes depression, and no systematic review of available evidence. AIMS: We systematically reviewed evidence on effects of reserpine on depressive and related symptoms (e.g. anxiety, suicidal ideation). METHOD: Electronic searches of MEDLINE, Embase and PsycINFO were conducted to identify studies up to 14 February 2021. Studies of any methodological design involving reserpine-treated and reserpine-untreated conditions, in any adult human population, were included and a narrative synthesis of findings was undertaken. Risk of bias (RoB) was examined using ROBINS-I. RESULTS: Of the 35 studies meeting inclusion criteria, 9 were randomised controlled trials. Eleven studies reported some depressogenic effects, 13 reported no effect and 11 reported putative antidepressant effects. Studies identifying depressive effects were more likely to examine people without psychiatric disorders at baseline, while studies identifying a potential antidepressant effect tended to treat fewer participants for shorter durations, at higher doses. Around one-third of studies conducted in people with psychiatric disorders showed beneficial effects on depression symptoms. 30/35 studies were at high RoB. CONCLUSIONS: Associations between reserpine and depression are inconsistent and limited by a lack of high-quality evidence. Due to reserpine's apparently complex effects, we urge nuance rather than simplicity surrounding the monoamine hypothesis of depression.
Assuntos
Depressão , Reserpina , Adulto , Humanos , Depressão/etiologia , Reserpina/efeitos adversos , Antidepressivos/efeitos adversos , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológicoRESUMO
Sigma-1 receptor (σ1R) ligands have been shown to be effective at relieving neuropathic and inflammatory pain, but have not yet been tested in experimental models of fibromyalgia. The objective of this study was to evaluate the effect of a σ1R antagonist (BD1063) compared to pregabalin. ICR-CD1 female mice were subjected to either six repeated injections of reserpine, to cause reserpine-induced myalgia (RIM6), or acidified saline intramuscular injections (ASI). In these two models, we evaluated the effect of BD1063 and pregabalin on thermal hypersensitivity, anxiety-like and depression-like behaviors, and on spinal cord gliosis. BD1063 exerted an antinociceptive effect on both reflexive (thermal hyperalgesia) and nonreflexive (anxiety- and depression-like) pain behaviors, and reduced spinal astroglial and microglial reactivity, following repeated treatment for 2 weeks. Interestingly, the effects of BD1063 were long-term, lasting several weeks after treatment discontinuation in both fibromyalgia-like models. Similar results were obtained with pregabalin, but the effects on pain behaviors lasted for a shorter length of time, and pregabalin did not significantly modulate spinal glial reactivity. The inhibitory and long-lasting effect of pharmacological blockade of σ1Rs on both sensory and affective dimensions of nociplastic-like pain and spinal cord gliosis in two experimental models of fibromyalgia support the application of this therapeutic strategy to treat fibromyalgia.
Assuntos
Analgésicos , Dor Crônica , Fibromialgia , Receptores sigma , Analgésicos/uso terapêutico , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Fibromialgia/tratamento farmacológico , Gliose , Hiperalgesia/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Pregabalina/uso terapêutico , Receptores sigma/antagonistas & inibidores , Reserpina/efeitos adversos , Receptor Sigma-1RESUMO
Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.
Assuntos
Cannabis , Fibromialgia , Analgésicos/efeitos adversos , Animais , Modelos Animais de Doenças , Dronabinol/efeitos adversos , Fibromialgia/induzido quimicamente , Fibromialgia/tratamento farmacológico , Hiperalgesia/induzido quimicamente , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Camundongos , Reserpina/efeitos adversosRESUMO
The pathological mechanisms of fibromyalgia (FM) are largely unknown. Recently, a rat reserpine-induced pain model showing exaggerated pain-related behaviors to mechanical and thermal stimuli has been used in FM research. However, the model has not been fully characterized. Here, we investigated nociceptive hypersensitivity to chemical stimuli and its spinal mechanisms to further characterize the model. The rat model was induced by administering reserpine to the nervous system. Nociceptive behaviors to chemical stimuli were quantified using the formalin pain test, and neuronal activation of the stimuli was examined using spinal c-Fos immunohistochemistry and electrophysiological recordings of superficial dorsal horn (SDH) neurons. The duration of pain-related behaviors was prolonged in both phases I (0-5 min) and II (10-60 min) and the interphase; and the number of c-Fos-immunoreactive nuclei increased in laminae I-II, III-IV, and V-VI at the spinal segments L3-L5 on the side ipsilateral to the formalin injection, and these factors were significantly and positively correlated. The action potentials of SDH neurons induced by formalin injection were markedly increased in rats treated with reserpine. These results demonstrate that pain-related behaviors are facilitated by noxious chemical stimuli in a rat reserpine-induced FM model, and that the behavioral hypersensitivity is associated with hyperactivation of SDH neurons.
Assuntos
Fibromialgia , Reserpina , Animais , Fibromialgia/induzido quimicamente , Formaldeído/efeitos adversos , Nociceptividade , Dor/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos , Ratos , Ratos Sprague-Dawley , Reserpina/efeitos adversos , Reserpina/análise , Medula EspinalRESUMO
Nociplastic pain, the third category of chronic pain, has emerged as a serious medical issue. Due to its significant negative influences on patients and society, high prevalence, and lack of sufficiently effective treatments, more efficacious therapies are required. This review highlights the potential therapeutic approaches identified in studies that used reserpine-induced myalgia (RIM) animal model that exhibits nociplastic pain-associated phenotypes. These studies have revealed that biologic processes including the chronic reduction of monoamines, increase of oxidative/nitrosative stresses and inflammatory mediators, upregulation of pronociceptive neurotransmitters and their receptors, increase of trophic factors, enhancement of the apoptotic pathway, sensory nerve sensitization, and activation of immune cells in central and/or peripheral regions underly the nociplastic pain-associated phenotypes in RIM animal model. Potential therapeutic approaches to nociplastic pain, i.e., 1) functional modification of specific molecules whose expression is distinctly altered following the chronic reduction of monoamines, 2) targeting the molecules that are responsible for other major categories of chronic pain (i.e., chronic inflammatory pain and neuropathic pain), 3) supplementation of nutrition to correct the disrupted nutritional balance, 4) improvement of physical constitution by natural substances, and 5) nonpharmacological interventions, have been identified. SIGNIFICANCE STATEMENT: Studies in reserpine-induced myalgia (RIM) animal model have revealed the pathologies that occur after the chronic reduction of monoamines and identified potential therapeutic approaches to nociplastic pain. Translation of their analgesic efficacy from RIM animal model to patients remains an issue to be addressed. Successful translation would lead to better therapies for nociplastic pain.
Assuntos
Dor Crônica , Fibromialgia , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/terapia , Modelos Animais de Doenças , Fibromialgia/induzido quimicamente , Fibromialgia/terapia , Humanos , Mialgia/tratamento farmacológico , Reserpina/efeitos adversosRESUMO
OBJECTIVES: Improving economy and well-being in developing nations like India has expanded life expectancy and changed the attention from transmittable to non transmittable diseases such as Parkinson's disease. Tabebuia impetiginosa has been utilized by cultivators as a general tonic, immunostimulant, adaptogen and also in motor disorders. The present investigation was to explore the antiparkinsonian activity of Tabebuia impetiginosa bark by experimental methods. MATERIALS AND METHODS: Control group-I was served with distilled water. Group-II was considered as pathological control [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2mg/nostrils i.n, Reserpine 40mg/kg s.c, Haloperidol 0.5mg/kg, i.p]. Group-III served with standard drug (Apomorphine 40mg/kg, s.c). Group IV and V received aqueous extract of Tabebuia impetiginosa bark in doses of 300 and 500mg/kg/day respectively. Tremor, hypokinesia, muscular rigidity, catatonia, postural immobility, postural instability and catalepsy were assessed for antiparkinsonian activity. RESULTS: The bark extract served group exhibited the increased levels of dopamine (5700±1.84ng/g) when compared to control groups (4300±3.17ng/g). The extract at both the doses displayed a significant reduction in postural flexion, moderate decrease in tremor, muscular rigidity and postural immobility scores but do not exhibit significant lowering of hypokinesia score in reserpine induced Parkinsonian model. The reduction in catatonia and catalepsy scores is more remarkable in case of high dose of extract (500mg/kg) compared to standard drug in Neuroleptic induced Parkinsonism. CONCLUSION: The findings demonstrate that Tabebuia impetiginosa bark extract has significant anti-cataleptic potentials and the antioxidant effect of the bark may also be a significant contributor to its antiparkinsonian activity.
Assuntos
Antipsicóticos , Catatonia , Tabebuia , Animais , Ratos , Casca de Planta , Dopamina/efeitos adversos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Antioxidantes/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Haloperidol/efeitos adversos , Reserpina/efeitos adversos , Hipocinesia , Apomorfina/efeitos adversos , Rigidez Muscular , Tremor , Antiparkinsonianos/efeitos adversos , Adjuvantes Imunológicos/efeitos adversos , Água , EncéfaloRESUMO
Historically, reserpine was widely used as an antihypertensive drug. However, severe motor and non-motor symptoms such as dyskinesia and depression led to the discontinuation of reserpine as a first-line treatment for hypertension. Reserpine functions by inhibiting vesicular monoamine transporter 2 (VMAT2), reducing sequestration of monoamines into synaptic vesicles. The consequent reduction in monoamines, most notably dopamine, serotonin and norepinephrine, in the central nervous system, causes well-defined symptoms such as catalepsy, hypoactivity and sedation in animals, and these motor and non-motor symptoms are well defined for reserpine treatment. However, no gross neuropathological changes in response to reserpine treatment have been reported previously in any animal model. In contrast, reducing VMAT2 expression in genetically modified VMAT2 LO mice leads to the production of âº-synuclein-positive aggregates and progressive nigrostriatal neuronal loss. These VMAT2 LO mice have reduced VMAT2 functionality during critical brain developmental stages and this could be the key to producing a reserpine model with matching histopathologies. The aim of this study was therefore to investigate the effect of neonatal reserpine administration on brain histology. We report here that a single dose of 5 mg kg-1 reserpine administered subcutaneously to neonatal rats on postnatal day 3 leads to widespread neuronal loss in various brain regions including the substantia nigra pars compacta, ventral tegmental area, striatum, hippocampus, locus coeruleus, amygdala and cerebral cortex, and the presence of âº-synuclein-positive inclusions in the substantia nigra pars compacta and the dorsal striatum within 30 days of administration.
Assuntos
Encéfalo/efeitos dos fármacos , Corpos de Inclusão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reserpina/efeitos adversos , alfa-Sinucleína/metabolismo , Animais , Encéfalo/patologia , Feminino , Corpos de Inclusão/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Reserpina/administração & dosagemRESUMO
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with various symptoms, such as depression, pain, and fatigue. To date, the pathological mechanisms and therapeutics remain uncertain. The purpose of this study was to investigate the effect of myelophil (MYP), composed of Astragali Radix and Salviaemiltiorrhizae Radix, on depression, pain, and fatigue behaviors and its underlying mechanisms. Reserpine (2 mg/kg for 10 days, intraperitoneally) induced depression, pain, and fatigue behaviors in mice. MYP treatment (100 mg/kg for 10 days, intragastrically) significantly improved depression behaviors, mechanical and thermal hypersensitivity, and fatigue behavior. MYP treatment regulated the expression of c-Fos, 5-HT1A/B receptors, and transforming growth factor ß (TGF-ß) in the brain, especially in the motor cortex, hippocampus, and nucleus of the solitary tract. MYP treatment decreased ionized calcium binding adapter molecule 1 (Iba1) expression in the hippocampus and increased tyrosine hydroxylase (TH) expression and the levels of dopamine and serotonin in the striatum. MYP treatment altered inflammatory and anti-oxidative-related mRNA expression in the spleen and liver. In conclusion, MYP was effective in recovering major symptoms of ME/CFS and was associated with the regulation of dopaminergic and serotonergic pathways and TGF-ß expression in the brain, as well as anti-inflammatory and anti-oxidant mechanisms in internal organs.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Síndrome de Fadiga Crônica/tratamento farmacológico , Hipocampo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/biossíntese , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/análise , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/biossíntese , Proteínas Proto-Oncogênicas c-fos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Reserpina/efeitos adversos , Serotonina/análise , Fator de Crescimento Transformador beta1/metabolismo , Tirosina 3-Mono-Oxigenase/biossínteseRESUMO
Depression is the most frequent affective disorder and is the leading cause of disability worldwide. In order to screen antidepressants and explore molecular mechanisms, a variety of animal models were used in experiments, but there is no reliable high-throughput screening method. Zebrafish is a common model organism for mental illness such as depression. In our research, we established chronic unpredictable mild stress (CUMS) models in C57BL/6 mice and zebrafish; the similarities in behavior and pathology suggest that zebrafish can replace rodents as high-throughput screening organisms. Stress mice (ip., 1 mg/kg/d, 3 days) and zebrafish (10 mg/L, 20 min) were treated with reserpine. As a result, reserpine caused depression-like behavior in mice, which was consistent with the results of the CUMS mice model. Additionally, reserpine reduced the locomotor ability and exploratory behavior of zebrafish, which was consistent with the results of the CUMS zebrafish model. Further analysis of the metabolic differences showed that the reserpine-induced zebrafish depression model was similar to the reserpine mice model and the CUMS mice model in the tyrosine metabolism pathway. The above results showed that the reserpine-induced depression zebrafish model was similar to the CUMS model from phenotype to internal metabolic changes and can replace the CUMS model for antidepressants screening. Moreover, the results from this model were obtained in a short time, which can shorten the cycle of drug screening and achieve high-throughput screening. Therefore, we believe it is a reliable high-throughput screening model.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Estresse Psicológico , Animais , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Reserpina/efeitos adversos , Reserpina/farmacologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia , Peixe-ZebraRESUMO
Fibromyalgia (FM) is one of the most common musculoskeletal pain conditions. Although the aetiology of FM is still unknown, mitochondrial dysfunction and the overproduction of reactive oxygen intermediates (ROI) are common characteristics in its pathogenesis. The reserpine experimental model can induce FM-related symptoms in rodents by depleting biogenic amines. However, it is unclear whether reserpine causes other pathophysiologic characteristics of FM. So far, no one has investigated the relevance of mitochondrial dysfunction in the reserpine-induced experimental FM model using protection- and insult-based mitochondrial modulators. Reserpine (1 mg/kg) was subcutaneously injected once daily for three consecutive days in male Swiss mice. We carried out analyses of reserpine-induced FM-related symptoms, and their modulation by using mitochondrial insult on ATP synthesis (oligomycin; 1 mg/kg, intraperitoneally) or mitochondrial protection (coenzyme Q10; 150 mg/kg/5 days, orally). We also evaluated the effect of reserpine on mitochondrial function using high-resolution respirometry and oxidative status. Reserpine caused nociception, loss in muscle strength, and anxiety- and depressive-like behaviours in mice that were consistent with clinical symptoms of FM, without inducing body weight and temperature alterations or motor impairment. Reserpine-induced FM-related symptoms were increased by oligomycin and reduced by coenzyme Q10 treatment. Reserpine caused mitochondrial dysfunction by negatively modulating the electron transport system and mitochondrial respiration (ATP synthesis) mainly in oxidative muscles and the spinal cord. These results support the role of mitochondria in mediating oxidative stress and FM symptoms in this model. In this way, reserpine-inducing mitochondrial dysfunction and increased production of ROI contribute to the development and maintenance of nociceptive, fatigue, and depressive-like behaviours.
Assuntos
Fibromialgia/induzido quimicamente , Fibromialgia/patologia , Mitocôndrias/patologia , Reserpina/efeitos adversos , Animais , Comportamento Animal , Depressão/complicações , Depressão/fisiopatologia , Modelos Animais de Doenças , Fadiga/complicações , Fadiga/fisiopatologia , Fibromialgia/fisiopatologia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Músculos/efeitos dos fármacos , Músculos/patologia , Nociceptividade/efeitos dos fármacos , Oxirredução , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMO
Fibromyalgia-associated chronic pain occurring without organic causes exerts negative effects on patients' quality of life, thereby necessitating the development of superior drugs. Since non-organic pain in patients with fibromyalgia occurs without external stimuli, an endpoint measure that reflects patients' spontaneous pain should be implemented in preclinical research. The present study is the first to apply the rat grimace scale (RGS), a facial expression-dependent measure developed for quantifying spontaneous pain, to the rat with reserpine-induced myalgia, an animal model of fibromyalgia exhibiting non-organic pain. Animals were videotaped and still images of facial expressions were captured and scored in a blind fashion. The reserpine-induced myalgia rats exhibited a significant increase in the RGS score, which was sustained for 2 weeks or more after the induction of fibromyalgia-like state by reserpine injection. The period of RGS score elevation was similar to that of reduced paw withdrawal threshold (PWT) measured using the von Frey filament test, a conventional measure of evoked pain. The elevated RGS score and the decreased PWT were relieved by gabapentin (an α2δ subunit ligand) and duloxetine (a serotonin and noradrenaline reuptake inhibitor), but not by diclofenac (a nonsteroidal anti-inflammatory drug), buprenorphine (a mu-opioid receptor agonist), or diazepam (a benzodiazepine). The present study suggests that facial expressions in reserpine-induced myalgia rats simulate non-organic pain occurring spontaneously in patients with fibromyalgia. This finding achieves a coordination of pain measures between the animal model and patients with fibromyalgia and would improve the translation of analgesic efficacies between them.
Assuntos
Expressão Facial , Fibromialgia/induzido quimicamente , Fibromialgia/complicações , Dor/complicações , Dor/psicologia , Reserpina/efeitos adversos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Dor/tratamento farmacológico , Ratos , Ratos Sprague-DawleyRESUMO
Functional somatic syndromes (FSS), a clinical condition manifesting a variety of unexplained somatic symptoms, has been proposed as an inclusive nosology encompassing individual syndromes such as fibromyalgia syndrome and irritable bowel syndrome. Accumulating evidence suggests that disturbance of the endogenous monoamine system could be involved in the aetiology of FSS. Therefore, the purpose of present study was to investigate whether the disturbance of the monoamine system would cause FSS-associated symptomatology in mice. The optimal dose of reserpine, an inducer of endogenous monoamines reduction, was first explored in mice. General body condition (body weight, rectal temperature, and ptosis) and FSS-associated symptomatology (paw withdrawal threshold, small intestinal transit, and locomotor activity) were measured. The concentration of monoamines was measured in central and peripheral tissues. Mice dosed with reserpine (0.25â¯mg/kgâ¯s.c., once daily for 3 consecutive days) exhibited a decrease in paw withdrawal threshold, delay in small intestinal transit, and reduction of locomotor activity without deterioration of general body condition on day 5 after the first reserpine injection. The concentration of monoamines was decreased in the central nervous system and skeletal muscle, but not in the small intestine. A reserpine dose of 0.5â¯mg/kg or more caused deterioration of general body condition. In conclusion, the optimal protocol of reserpine treatment for inducing pain symptom without deterioration of general physical condition is 0.25â¯mg/kgâ¯s.c., once daily for 3 consecutive days in mice. This protocol causes not only pain but also FSS-associated symptomatology which are associated with disruption of the endogenous monoamine system. The reserpine-treated animal may be useful for the research of not only fibromyalgia syndrome but also FSS, especially for the research focusing on the hypothesis that FSS is associated with the disturbance of endogenous monoamine system.
Assuntos
Monoaminas Biogênicas/fisiologia , Trânsito Gastrointestinal/fisiologia , Locomoção/fisiologia , Limiar da Dor/fisiologia , Reserpina/efeitos adversos , Transtornos Somatoformes/fisiopatologia , Animais , Monoaminas Biogênicas/metabolismo , Blefaroptose/induzido quimicamente , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Esquema de Medicação , Intestino Delgado/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Transtornos Somatoformes/induzido quimicamenteRESUMO
BACKGROUND: When patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered. OBJECTIVE: The aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward. DISCUSSION: Akathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.
Assuntos
Ansiedade/etiologia , Agitação Psicomotora/complicações , Agitação Psicomotora/diagnóstico , Adulto , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Antieméticos/efeitos adversos , Antieméticos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Ansiedade/diagnóstico , Buspirona/efeitos adversos , Buspirona/uso terapêutico , Cinarizina/efeitos adversos , Cinarizina/uso terapêutico , Diltiazem/efeitos adversos , Diltiazem/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Humanos , Metildopa/efeitos adversos , Metildopa/uso terapêutico , Agitação Psicomotora/etiologia , Reserpina/efeitos adversos , Reserpina/uso terapêutico , Ideação SuicidaRESUMO
BACKGROUND: In the 1940s reserpine, refined from a plant extract that had been used for centuries, began to be used as a treatment for people with mental disorders and was one of the very first antipsychotic drugs. Its irreversible pharmacological potency and adverse effects meant that it has been withdrawn in the UK and its role has been superceded by 'newer' compounds. The effects of reserpine are of historical interest although there are some reports of it still being used in highly specialist situations in psychiatry. Chlorpromazine is also an old drug but it is still used for treatment of people with schizophrenia. OBJECTIVES: To investigate the effects of two old medications (reserpine and chlorpromazine) for people with schizophrenia. Reserpine is now rarely used while chlorpromazine remains on the essential list of drugs of the World Health Organization (WHO). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (24 March 2016). SELECTION CRITERIA: We included randomised clinical trials focusing on chlorpromazine versus reserpine for schizophrenia that presented useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The review currently includes nine studies with an average 60 participants per study. All of these studies are now over 60 years old, conducted between 1955 and 1962. When chlorpromazine was compared with reserpine for people with schizophrenia, improvement in global state was better at short term for those receiving chlorpromazine (n = 781, 6 RCTs, RR 'not improved' 0.75 95% CI 0.62 to 0.92, low-quality evidence). Short-term improvement in paranoid distortion was measured using the Multidimensional Scale for Rating Psychiatric Patients (MSRPP). Data showed no clear difference between treatment groups (n = 19, 1 RCT, RR 1.33 95% CI 0.62 to 2.89, very low-quality evidence). There was no difference in functioning: occupational adjustment, medium term (n = 40, 1 RCT, RR 0.83 95% CI 0.47 to 1.47, moderate-quality evidence) and general behaviour (n = 98, 1 RCT, RR 0.79 CI 0.41 to 1.53, moderate-quality evidence). Adverse events were poorly reported. For 'toxic reaction' there was, again, no obvious difference between the two compounds (n = 210, 3 RCTs, RR 1.68 95% CI 0.43 to 6.54, moderate-quality evidence), and this also applied to leaving the study early (n = 229, 4 RCTs, RR 1.16 95% CI 0.94 to 1.42, moderate-quality evidence). AUTHORS' CONCLUSIONS: Judged by standards of today, the evidence is largely of limited quality. However, some of these 1950s studies are remarkable in their foresight and clarity. Reserpine did have some effect on global state - but chlorpromazine did seem to perform better. Important issues regarding adverse effects were not really addressed by these trials. Chlorpromazine remains on the WHO list of essential drugs. Reserpine is now almost obsolete, although, probably as a result of evidence other than that reported in the pioneering trials used in this review.